Persistence of precursor cells of squamous metaplasia in preneoplastic mammary outgrowth lines from mice.

The preneoplastic state is without apparent effect on the induction or prevention of epidermidalization in transplanted mammary outgrowth lines. Development of squamous metaplasia and differentiation (keratinization) were induced in organ cultures of three hyperplastic alveolar and ductular mammary outgrowth lines (D1, MH5, and MH9) that had been extensively passaged in gland-free mammary fat pads of BALB/c virgin mice. The induction was elicited by the mixture of dibutyryl cyclic AMP (0.1 mM), prostaglandins E1, E2, and B1 (each 5 micrograms/ml), and papaverine (1 microM) or by a tenfold higher concentration of dibutyryl cyclic AMP (1 mM) alone for 9 days. The retinoid 2-retinylidene-5,5-dimethyl-1,3-cyclohexanedione at 1 microM and the phorbol ester phorbol 12,13-didecanoate at 10 microM each blocked the induction process. The parameters of the induction and its prevention were analogous in many ways to those previously found with cultures of normal mammary glands of mice and humans, as well as of mouse prostate glands and chick embryo skin. The metaplastic squamous cells that developed in the cultured mammary outgrowths did not proliferate in gland-free mammary fat pads, possibly because the cells were terminally committed or because of insufficient inducers. In contrast, the alveolar and ductular epithelia in the same outgrowths have a transplantable pool of generative cells with the ability to undergo continual proliferation and development. The finding of precursor cells with the potential for epidermoid development and differentiation in the preneoplastic alveolar and ductular outgrowths, despite their extensive serial transplantations, is supportive of the existence of a common or closely associated pool of cells with the ability to develop either into squamous or alveolar mammary epithelium.